Imidazole derivatives of the class 1-(.beta.-aryl)ethylimidazole ethers useful for their antifungal properties are disclosed in U.S. Pat. No. 3,717,655, incorporated herein by reference for its teaching of the preparation and use of such compounds. As described in this patent, imidazole derivatives of the defined class have the formula: ##STR1## and the therapeutically active acid addition salts thereof, wherein:
R, R.sub.1 and R.sub.2 are each a member selected from the group consisting of hydrogen and lower alkyl; n is the integer 1 or 2;
Ar is a member selected from the group consisting of phenyl, mono-, di- and tri-halophenyl, lower alkylphenyl, lower alkoxyphenyl, thienyl and halothienyl;
Ar' is a member selected from the group consisting of phenyl, mono-, di- and tri-halophenyl, mono- and di-(lower alkyl) phenyl, lower alkoxyphenyl and cyanophenyl;
R' is a member selected from the group consisting of hydrogen, methyl and ethyl; and
R" is a member selected from the group consisting of hydrogen and methyl.
The '655 patent further discloses that compositions comprising such imidazole derivatives as the active ingredient in a solvent or a solid, semi-solid or liquid diluent or carrier provide an effective method of combatting fungus growth. According to the patent, "The subject compounds can be used in suitable solvents or diluents, in the form of emulsions, suspensions, dispersions or ointment, on suitable solid or semi-solid carrier substances, in ordinary or synthetic soaps, detergents or dispersion media, if desired, together with other compounds having arachnicidal, insecticidal, ovicidal, fungicidal and/or bactericidal effects, or together with inactive additives."
"Inert solvents used for the production of liquid preparations should preferably not be readily inflammable and should be as far as possible odorless and as far as possible non-toxic to warm-blooded animals or plants in the relevant surroundings. Solvents suitable for this purpose are high-boiling oils, for example, of vegetable origin, and lower-boiling solvents with a flash point of at least 30.degree. C., such as, for example, isopropanol dimethylsulfoxide, hydrogenated naphthalenes and alkylated napthalenes. It is, of course, also possible to use mixtures of solvents. Solutions can be prepared in the usual way, if necessary, with assistance of solution promoters. Other liquid forms which can be used consist of emulsions or suspensions of the active compound in water or suitable inert solvents, or also concentrates for preparing such emulsions, which can be directly adjusted to the required concentration. For this purpose, the active ingredient is, for example, mixed with a dispersing or emulsifying agent. The active component can also be dissolved or dispersed in a suitable inert solvent and mixed simultaneously or subsequently with a dispersing or emulsifying agent."
"When the subject compounds are employed in combination with suitable carriers, e.g., in solution, suspension, duct, powder, ointment, emulsion, and the like forms, a high activity over a very high range of dilution is observed. For example, concentrations of the active ingredient ranging from 0.1-10 percent by weight, based on the weight of composition employed, have been found effective in combatting fungi or bacteria. Of course, higher concentrations may also be employed as warranted by the particular situation."
An example of an imidazole solution is given in Example LX of the '655 patent where five parts of 1-[p-chloro-.beta.-(2,6-dichlorobenzyloxy)phenethyl] imidazole are dissolved in 95 parts of alkylated naphthalene and used as a spray for the treatment of fungus infected subjects or on walls, floors or other objects to prevent infection by fungi. Such solutions of the imidazole derivatives, while effective antifungal compositions, are obviously not suitable for dermatological use due to the presence of the strong organic solvent which has an irritating and defatting effect on tissue.
A preferred imidazole derivative for use in the present invention is 1-[2,4-dichloro-.beta.-(2,4-dichlorobenzyloxy)phenethyl] imidazole nitrate which has the common name miconazole nitrate. The solubility of miconazole nitrate in water is 0.03% and in ethanol 0.76% weight/volume. The solubility is thus too low in such solvents to provide the desired concentration of at least one percent pharmaceutical active agent in solution for use as a dermatological product.
It is accordingly an object of the present invention to provide a new solvent system for compounds of the class 1-(.beta.-aryl)ethyl-imidazole ethers. It is a further object to provide a new solvent system in which such imidazole ethers are soluble to the extent of at least one percent. It is a yet further object of this invention to provide a dermatological antifungal solution comprising at least one percent of a 1-(.beta.-aryl)ethyl-imidazole ether derivative in a pharmaceutically acceptable solvent system. A still further object of this invention is to provide a dermatological antifungal solution comprising at least one percent miconazole or miconazole nitrate in a novel solvent system. These and other objects of this invention will be apparent from the ensuing description and claims.